Citations

Objective The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single‐pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation. Methods Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier. Results Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus‐ventral anterior nucleus junction. DBS delivered for >1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well‐connected seizure networks. Interpretation BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large‐scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748–760

Background α‐Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10‐year survival. Methods In this retrospective cohort, blinded clinicians scored calcification on computed tomography (0–10 scale: aorta 6 points, iliac 4 points). Plasma klotho was measured by ELISA; endothelial progenitor cell subsets were quantified via flow cytometry. Mortality data were obtained from the Minnesota Death Registry. Results This study included 148 participants (mean age 72.4±9.6 years; 41% female). Median calcification score was 3 (interquartile range, 1–5). Patients with low calcification had higher Klotho levels (669 [567–841] versus 556 [457–678] pg/mL; P <0.01), with Klotho inversely correlated with calcification (r=−0.315, P <0.01). Stratified by calcification location and severity, the highest Klotho levels were seen in patients without aortic or iliac calcification ( P =0.015). Over 10 years, low Klotho was independently associated with higher mortality (hazard ratio [HR], 3.056 [95% CI 1.288–7.878]; P =0.014). Klotho inversely correlated with mature osteocalcin‐positive EPCs; B=−0.16 (95% CI, −0.29 to −0.02; P =0.027). Immunohistochemistry and immunofluorescence confirmed endothelial Klotho expression in internal mammary artery. Conclusions Lower circulating Klotho levels are associated with increased aortoiliac calcification and higher 10‐year mortality, supporting a role for Klotho in vascular aging.

Purpose of review Cardiac amyloidosis is an infiltrative cardiomyopathy with characteristic echocardiographic findings. Echocardiography is the initial imaging test to identify restrictive cardiomyopathies, and timely diagnosis is important for treatment and prognosis. This review outlines key echocardiographic “red flags,” structural and functional findings, and emerging diagnostic tools that enhance early recognition and monitoring of cardiac amyloidosis. Recent findings Classic echocardiographic red flags for cardiac amyloidosis include increased ventricular wall thickness, biatrial enlargement, pericardial effusion, and a granular myocardial appearance. Tissue Doppler imaging shows reduced mitral annular velocities, while advanced disease presents with restrictive filling patterns. Global longitudinal strain with apical sparing is a hallmark finding that distinguishes cardiac amyloidosis from other cardiomyopathies. Left atrial strain has been proposed as a prognostic marker for thromboembolism in cardiac amyloidosis. Evidence shows variability in strain measurements across different vendors, which is an important consideration when comparing results between institutions in both research and clinical practice. Echocardiography can be used in conjunction with multimodal imaging techniques in order to monitor disease progression. Summary Echocardiography is the initial diagnostic test of choice and several findings can suggest cardiac amyloidosis. Advances in echocardiographic techniques have enabled earlier detection of cardiac involvement and now play a central role in both diagnosis and ongoing treatment monitoring.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P &amp;lt; .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P &amp;lt; .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Background: Coronary microvascular dysfunction (CMD) is a common cause of angina with non-obstructive coronary arteries (ANOCA), but its role in patients with a history of myocardial infarction with non-obstructive coronary arteries (MINOCA) is much less understood. We investigated the incidence of major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing invasive assessment for CMD, divided into patients with MINOCA versus patients with ANOCA. We hypothesized that CMD would be common in both groups. Methods: Serial patients undergoing invasive coronary provocation testing between 2012 and 2022 were divided into MINOCA (n=76) or ANOCA (n=561). Doppler study was performed in the left anterior descending artery. CMD was defined as either coronary flow reserve (CFR) <2.5 with adenosine or <50% increase in flow with acetylcholine. Patients were followed prospectively through 2025. Incidence of MACCE (cardiac death, non-fatal MI, hospitalization for heart failure, urgent revascularization, and stroke) was compared between MINOCA and ANOCA and further analyzed by CMD status. Kaplan-Meier curves were constructed and Cox proportional hazards models were used to estimate hazard ratios (HRs). Results: Among patients with MINOCA, 53 of 76 (70%) had CMD, compared to 363 of 561 (65%) with ANOCA. Invasive provocation testing was performed a median of 163 days (IQR 13 – 255 days) after the MI in the MINOCA group. Patients were then followed for a median of 4.4 years (IQR 3.0 – 6.9 years). MACCE-free survival was significantly lower in patients with MINOCA compared to those with ANOCA (HR = 3.57, p < 0.001; Figure 1). The major contributor to MACCE was non-fatal MI in MINOCA (24%) and heart failure hospitalization in ANOCA (6%). The presence of CMD was associated with worse prognosis in both MINOCA (HR = 3.76, p = 0.02) and ANOCA (HR = 8.35, p < 0.001; Figure 2). Conclusions: Patients with MINOCA experience significantly higher long-term risk of major adverse events compared to those with ANOCA. CMD is common in both groups and is independently associated with worse outcomes. Specifically, patients with CMD had higher rates of MACCE over time, regardless of whether they presented with MINOCA or ANOCA. Invasive assessment of CMD in patients with myocardial infarction and non-obstructive coronary arteries may improve risk stratification and inform management strategies in these understudied populations

Introduction: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema, hypoxia and systemic inflammation. The presence and clinical implications of a high cardiac output state in patients with ARDS remain unknown given the lack of invasive hemodynamic monitoring in most patients with ARDS. Hypothesis: A subset of patients with ARDS will have high output heart failure with high cardiac output and elevated pulmonary capillary wedge pressure (PAWP) representing a unique subphenotype of ARDS. Methods: Patients from the Comparison of Two Fluid-Management Strategies in Acute Lung Injury (FACTT) Trial were stratified according to baseline cardiac output states and filling pressures: HOLHF (high-output with left heart failure) was defined as cardiac index (CI) ≥ 4 L/min/m 2 and PAWP ≥ 15 mmHg; HOnoLHF (high-output without left heart failure) as CI ≥ 4 L/min/m 2 and PAWP < 15 mmHg; and NOHO (non-high-output) as CI < 4 L/min/m 2 . Hemodynamics, oxygenation, metabolic demand (VO 2 ) and clinical outcomes were compared across groups. Results: Of the 399 patients included, high-output states were present in 52% of all patients (Figure 1). High-output cohorts demonstrated higher myocardial workload, lower systemic vascular resistance (SVR), lower pulsatile arterial load, higher VO 2 and more impaired systemic O 2 utilization despite the highest peripheral O 2 delivery compared to NOHO (Table). Among the high-output cohorts, the HOLHF cohort demonstrated higher right ventricular stroke work (25.2 ± 12.1 vs. 20.3 ± 12.3, P<0.001), worse A-a gradient (326.0 ± 136.5 vs. 276.1 ± 114.7, P=0.048) and higher VO 2 (382.3 ± 234.2 vs. 289.8 ± 171.7, P<0.001) compared to HOnoLHF. Increasing cardiac output was individually related to decreasing SVR (r=-0.742, P<0.001) and increasing VO 2 (r=0.565, P<0.001) (Figure 2). When adjusted, both variables remained strongly related to increasing cardiac output (P<0.001). There were no significant differences among the cohorts with respect to refractory hypoxia and mortality. Conclusions: High-output states in ARDS are prevalent and underrecognized. Such states appear to be driven by arterial vasodilatation and heightened VO 2 with additional manifestations of increased myocardial workload and inefficient peripheral utilization with impaired systemic O 2 utilization. Whether specific strategies to mitigate the high output state might improve gas exchange, hypoxia and outcomes in patients with HOLHF and ARDS requires further study.

Background: An increasing recognition of angina and nonobstructive coronary artery disease (ANOCA) underscores the importance of this patient group. While inflammation is a well-established key driver in the initiation and progression of atherosclerosis, its role in early stage is less clear. The current study was designed to assess the predictive value of monocyte-lymphocyte ratio(MLR) in comparison with hs-CRP in these patients. Method: This observational cohort study included patients with chest pain and nonobstructive coronary artery disease <40% stenosis in major coronary arteries on clinically indicated elective coronary angiography who underwent invasive physiological coronary reactivity testing for evaluation of coronary vasomotor function between 1997-2021. Preprocedural MLR was categorized as high (≥0.30) or low (<0.30) using the best cutoff value for predicting major adverse cardiovascular and cerebrovascular events (MACCE) determined by ROC curves. Preprocedural Hs-CRP levels ≥1 and <1 mg/L were classified as high or low, respectively. MACCE comprised cardiovascular death, nonfatal myocardial infarction, heart failure, stroke, and late revascularization. Kaplan-Meier plots, Log-rank test, and Cox regression analysis were used for analysis. Result: Among 892 patients (median age 52 [IQR: 43- 61] years, 69% females), 40% had high MLR and 49% had high hs-CRP, respectively. Over a 10-year follow-up, 125 patients (14%) experienced MACCE. In univariable analysis, high MLR level ( p < 0.001 ) and high hs-CRP ( p = 0.045) were associated with worse outcomes. (Figure 1) In multivariate Cox regression after adjusting for age, body mass index, creatinine, hypertension, hyperlipidemia, and diabetes mellitus, MLR remained a significant predictor of MACCE (HR=1.75, 95% CI=1.20- 2.55, p = 0.004), whereas hs-CRP lost its significance (HR=1.26, 95% CI=0.857- 1.848, p=0.241). Stratifying patients into four groups of high MLR/high hs-CRP (21%), high MLR/low hs-CRP (19%), low MLR/high hs-CRP (28%), and low MLR/low hs-CRP (32%) revealed that high MLR was associated with increased MACCE in both groups with high and low hs-CRP, while in both high MLR and low MLR groups, hs-CRP levels made no difference in MACCE incidences. (Figure 2). Conclusion: elevated MLR is a strong independent predictor of MACCE in patients with ANOCA, superior to hs-CRP. These findings highlight the potential of MLR as a valuable, readily available marker for risk stratification in early atherosclerosis.

Introduction: Photoplethysmography-based (PPG) devices represent a significant advancement in noninvasive cardiovascular monitoring. These cuffless technologies enable assessment of hemodynamic parameters with improved comfort, usability and compliance. Modern PPG systems have expanded their capabilities to include advanced metrics such as systemic vascular resistance (SVR) and cardiac output (CO). Many antihypertensive drugs lower blood pressure by reducing SVR through vasodilatation of the systemic and renal vasculature. Limited data is available on SVR during ambulatory monitoring. PPG devices become more common as they allow us to assess SVR in real life, in ambulatory blood pressure monitoring (ABPM) patients. Aim: To evaluate and compare SVR using the Biobeat (WP613) device across patient groups. Methods: Adults from the Hypertension Clinic at University of Miami, Florida, from Aug. 2023–Jan. 2025 underwent 24-h ABPM monitoring using Biobeat device. Patient data was matched with Biobeat. PPG data was available every 15 minutes; The raw data included SBP and DBP, the heart rate, stroke volume, CO and SVR. Results: A total of 539 patients underwent PPG ABPM during the study period. The median was 62 (IQR 54, 71) years, with 57% females (Tab 1) . Patients were defined as hypertensive per AHA 2017 guidelines [SBP≥130 and DBP≥80 mmHg]. Overall, 265 patients were classified as having normal BP, 95 as having isolated systolic hypertension, and 179 as having mixed hypertension. Within the Mix-HTN group, 42 patients had isolated diastolic hypertension and the remaining 137 systolic and diastolic hypertension (Fig 2) . In subgroup analysis (Fig 3); SVR was significantly different between the groups: lowerst in No/C-HTN and highest in Mix-HTN. particularly among the mixed-hypertension group, SVR was higher in the Systolic and Diastolic HTN compared to the Isolated diastolic HTN group. Among the No/C-HTN group, 60 patients were not hypertensives and 205, were hypertensives on at least 1 drug. The SVR was not statistically significant between these 2 subgroups, suggesting that SVR may be a helpful target biomarker used to up-titrate antihypertensives. Conclusion: PPG devices offer a valuable enhancement to conventional ABPM by providing additional physiological measurements such as SVR that can help differentiate between various hypertension phenotypes and potentially provide personalized therapy that target the driver of hypertension.